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Published in: Journal of Experimental & Clinical Cancer Research 1/2014

Open Access 01-12-2014 | Research

Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non-muscle invasive bladder cancer

Authors: Ying-Li Lin, Yan-Ling Wang, Jian-Guo Ma, Wen-Ping Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2014

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Abstract

Background

PCDH8 is a novel tumor suppressor gene, and frequently inactivated by promoter methylation in human cancers. However, there is little information regarding PCDH8 methylation in non-muscle invasive bladder cancer (NMIBC). The aim of this study was to investigate the methylation status of PCDH8 in NMIBC and its clinical significance.

Methods

The methylation status of PCDH8 in 233 NMIBC tissues and 43 normal bladder epithelial tissues was examined by methylation-specific PCR (MSP), and then analyzed the correlations between PCDH8 methylation and clinicopatholocial features. Subsequently, Kaplan-Meier survival analysis and Multivariate Cox proportional hazard model analysis was used to investigate the correlation between PCDH8 methylation and prognosis of patients with NMIBC.

Results

PCDH8 methylation occurred frequently in NMIBC tissues than those in normal bladder epithelial tissues. In addition, PCDH8 methylation significantly correlated with advanced stage, high grade, larger tumor size, tumor recurrence and progression in NMIBC. Kaplan-Meier survival analysis revealed that patients with PCDH8 methylated have shorter recurrence-free survival, progression-free survival and five-year overall survival than patients with PCDH8 unmethylated. Multivariate analysis suggested that PCDH8 methylation was an independent prognostic biomarker for recurrence-free survival, progression-free survival and five-year overall survival simultaneously.

Conclusions

PCDH8 methylation may be associated with tumor progression and poor prognosis in NMIBC and may be used as a potential biomarker to predict the prognosis of patients with NMIBC.
Appendix
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Literature
1.
go back to reference Siegel R1, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 2013, 63 (1): 11-30. 10.3322/caac.21166.CrossRefPubMed Siegel R1, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 2013, 63 (1): 11-30. 10.3322/caac.21166.CrossRefPubMed
2.
go back to reference Kaufman DS, Shipley WU, Feldman AS: Bladder cancer. Lancet. 2009, 374 (9685): 239-249. 10.1016/S0140-6736(09)60491-8.CrossRefPubMed Kaufman DS, Shipley WU, Feldman AS: Bladder cancer. Lancet. 2009, 374 (9685): 239-249. 10.1016/S0140-6736(09)60491-8.CrossRefPubMed
3.
go back to reference Parkin DM: The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl. 2008, 218: 12-20. 10.1080/03008880802285032.CrossRefPubMed Parkin DM: The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl. 2008, 218: 12-20. 10.1080/03008880802285032.CrossRefPubMed
4.
go back to reference Ploeg M, Aben KK, Kiemeney LA: The present and future burden of urinary bladder cancer in the world. World J Urol. 2009, 27 (3): 289-293. 10.1007/s00345-009-0383-3.PubMedCentralCrossRefPubMed Ploeg M, Aben KK, Kiemeney LA: The present and future burden of urinary bladder cancer in the world. World J Urol. 2009, 27 (3): 289-293. 10.1007/s00345-009-0383-3.PubMedCentralCrossRefPubMed
5.
go back to reference Van den Bosch S, Alfred Witjes J: Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol. 2011, 60 (3): 493-500. 10.1016/j.eururo.2011.05.045.CrossRefPubMed Van den Bosch S, Alfred Witjes J: Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol. 2011, 60 (3): 493-500. 10.1016/j.eururo.2011.05.045.CrossRefPubMed
6.
go back to reference Van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, Witjes JA, Zlotta AR: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009, 56 (3): 430-442. 10.1016/j.eururo.2009.06.028.CrossRefPubMed Van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, Witjes JA, Zlotta AR: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009, 56 (3): 430-442. 10.1016/j.eururo.2009.06.028.CrossRefPubMed
7.
go back to reference Musquera M, Mengual L, Ribal MJ: Non-invasive diagnosis bladder cancer: new molecular markers and future perspectives. Arch Esp Urol. 2013, 66 (5): 487-494.PubMed Musquera M, Mengual L, Ribal MJ: Non-invasive diagnosis bladder cancer: new molecular markers and future perspectives. Arch Esp Urol. 2013, 66 (5): 487-494.PubMed
8.
go back to reference Galustian C: Tools to investigate biomarker expression in bladder cancer progression. BJU Int. 2013, 112 (3): 404-406. 10.1111/j.1464-410X.2013.11792.x.CrossRefPubMed Galustian C: Tools to investigate biomarker expression in bladder cancer progression. BJU Int. 2013, 112 (3): 404-406. 10.1111/j.1464-410X.2013.11792.x.CrossRefPubMed
9.
go back to reference Kandimalla R, van Tilborg AA, Zwarthoff EC: DNA methylation-based biomarkers in bladder cancer. Nat Rev Urol. 2013, 10 (6): 327-335. 10.1038/nrurol.2013.89.CrossRefPubMed Kandimalla R, van Tilborg AA, Zwarthoff EC: DNA methylation-based biomarkers in bladder cancer. Nat Rev Urol. 2013, 10 (6): 327-335. 10.1038/nrurol.2013.89.CrossRefPubMed
10.
go back to reference Kim WJ, Kim YJ: Epigenetics of bladder cancer. Methods Mol Biol. 2012, 863: 111-118. 10.1007/978-1-61779-612-8_6.CrossRefPubMed Kim WJ, Kim YJ: Epigenetics of bladder cancer. Methods Mol Biol. 2012, 863: 111-118. 10.1007/978-1-61779-612-8_6.CrossRefPubMed
13.
go back to reference Lin YL, Ma JH, Luo XL, Guan TY, Li ZG: Clinical significance of protocadherin-8 (PCDH8) promoter methylation in bladder cancer. J Int Med Res. 2013, 41 (1): 48-54. 10.1177/0300060513475571.CrossRefPubMed Lin YL, Ma JH, Luo XL, Guan TY, Li ZG: Clinical significance of protocadherin-8 (PCDH8) promoter methylation in bladder cancer. J Int Med Res. 2013, 41 (1): 48-54. 10.1177/0300060513475571.CrossRefPubMed
14.
go back to reference Zhang D, Zhao W, Liao X, Bi T, Li H, Che X: Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer. Oncol Rep. 2012, 28 (5): 1785-1791.PubMed Zhang D, Zhao W, Liao X, Bi T, Li H, Che X: Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer. Oncol Rep. 2012, 28 (5): 1785-1791.PubMed
15.
go back to reference Yu JS, Koujak S, Nagase S, Li CM, Su T, Wang X, Keniry M, Memeo L, Rojtman A, Mansukhani M, Hibshoosh H, Tycko B, Parsons R: PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene. 2008, 27 (34): 4657-4665. 10.1038/onc.2008.101.PubMedCentralCrossRefPubMed Yu JS, Koujak S, Nagase S, Li CM, Su T, Wang X, Keniry M, Memeo L, Rojtman A, Mansukhani M, Hibshoosh H, Tycko B, Parsons R: PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene. 2008, 27 (34): 4657-4665. 10.1038/onc.2008.101.PubMedCentralCrossRefPubMed
16.
go back to reference He D, Zeng Q, Ren G, Xiang T, Qian Y, Hu Q, Zhu J, Hong S, Hu G: Protocadherin8 is a functional tumor suppressor frequently inactivated by promoter methylation in nasopharyngeal carcinoma. Eur J Cancer Prev. 2012, 21 (6): 569-575. 10.1097/CEJ.0b013e328350b097.CrossRefPubMed He D, Zeng Q, Ren G, Xiang T, Qian Y, Hu Q, Zhu J, Hong S, Hu G: Protocadherin8 is a functional tumor suppressor frequently inactivated by promoter methylation in nasopharyngeal carcinoma. Eur J Cancer Prev. 2012, 21 (6): 569-575. 10.1097/CEJ.0b013e328350b097.CrossRefPubMed
17.
go back to reference Tang X, Yin X, Xiang T, Li H, Li F, Chen L, Ren G: Protocadherin 10 is frequently downregulated by promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer. Cancer Biomark. 2013, 12 (1): 11-19. Tang X, Yin X, Xiang T, Li H, Li F, Chen L, Ren G: Protocadherin 10 is frequently downregulated by promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer. Cancer Biomark. 2013, 12 (1): 11-19.
18.
go back to reference Lin YL, Li ZG, He ZK, Guan TY, Ma JG: Clinical and prognostic significance of protocadherin-10 (PCDH10) promoter methylation in bladder cancer. J Int Med Res. 2012, 40 (6): 2117-2123. 10.1177/030006051204000609.CrossRefPubMed Lin YL, Li ZG, He ZK, Guan TY, Ma JG: Clinical and prognostic significance of protocadherin-10 (PCDH10) promoter methylation in bladder cancer. J Int Med Res. 2012, 40 (6): 2117-2123. 10.1177/030006051204000609.CrossRefPubMed
19.
go back to reference Costa VL, Henrique R, Danielsen SA, Eknaes M, Patrício P, Morais A, Oliveira J, Lothe RA, Teixeira MR, Lind GE, Jerónimo C: TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics. 2011, 6 (9): 1120-1130. 10.4161/epi.6.9.16376.CrossRefPubMed Costa VL, Henrique R, Danielsen SA, Eknaes M, Patrício P, Morais A, Oliveira J, Lothe RA, Teixeira MR, Lind GE, Jerónimo C: TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics. 2011, 6 (9): 1120-1130. 10.4161/epi.6.9.16376.CrossRefPubMed
20.
go back to reference Yang Y, Liu J, Li X, Li JC: PCDH17 gene promoter demethylation and cell cycle arrest by genistein in gastric cancer. Histol Histopathol. 2012, 27 (2): 217-224.PubMed Yang Y, Liu J, Li X, Li JC: PCDH17 gene promoter demethylation and cell cycle arrest by genistein in gastric cancer. Histol Histopathol. 2012, 27 (2): 217-224.PubMed
21.
go back to reference Imoto I, Izumi H, Yokoi S, Hosoda H, Shibata T, Hosoda F, Ohki M, Hirohashi S, Inazawa J: Frequent silencing of the candidate tumor suppressor PCDH20 by epigenetic mechanism in non-small-cell lung cancers. Cancer Res. 2006, 66 (9): 4617-4626. 10.1158/0008-5472.CAN-05-4437.CrossRefPubMed Imoto I, Izumi H, Yokoi S, Hosoda H, Shibata T, Hosoda F, Ohki M, Hirohashi S, Inazawa J: Frequent silencing of the candidate tumor suppressor PCDH20 by epigenetic mechanism in non-small-cell lung cancers. Cancer Res. 2006, 66 (9): 4617-4626. 10.1158/0008-5472.CAN-05-4437.CrossRefPubMed
22.
go back to reference Greene FL: The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg. 2002, 87 (7): 13-15.PubMed Greene FL: The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg. 2002, 87 (7): 13-15.PubMed
23.
go back to reference Oosterlinck W, Lobel B, Jakse G, Malmström PU, Stöckle M, Sternberg C: Guidelines on bladder cancer. Eur Urol. 2002, 41 (2): 105-112. 10.1016/S0302-2838(01)00026-4.CrossRefPubMed Oosterlinck W, Lobel B, Jakse G, Malmström PU, Stöckle M, Sternberg C: Guidelines on bladder cancer. Eur Urol. 2002, 41 (2): 105-112. 10.1016/S0302-2838(01)00026-4.CrossRefPubMed
24.
go back to reference Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J, Rouprêt M: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011, 59 (6): 997-1008. 10.1016/j.eururo.2011.03.017.CrossRefPubMed Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J, Rouprêt M: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011, 59 (6): 997-1008. 10.1016/j.eururo.2011.03.017.CrossRefPubMed
25.
go back to reference Li H, Wang J, Xiao W, Xia D, Lang B, Wang T, Guo X, Hu Z, Ye Z, Xu H: Epigenetic inactivation of KLF4 is associated with urothelial cancer progression and early recurrence. J Urol. 2014, 191 (2): 493-501. 10.1016/j.juro.2013.08.087.CrossRefPubMed Li H, Wang J, Xiao W, Xia D, Lang B, Wang T, Guo X, Hu Z, Ye Z, Xu H: Epigenetic inactivation of KLF4 is associated with urothelial cancer progression and early recurrence. J Urol. 2014, 191 (2): 493-501. 10.1016/j.juro.2013.08.087.CrossRefPubMed
26.
go back to reference Casadio V, Molinari C, Calistri D, Tebaldi M, Gunelli R, Serra L, Falcini F, Zingaretti C, Silvestrini R, Amadori D, Zoli W: DNA Methylation profiles as predictors of recurrence in non muscle invasive bladder cancer: an MS-MLPA approach. J Exp Clin Cancer Res. 2013, 32 (1): 94-10.1186/1756-9966-32-94.PubMedCentralCrossRefPubMed Casadio V, Molinari C, Calistri D, Tebaldi M, Gunelli R, Serra L, Falcini F, Zingaretti C, Silvestrini R, Amadori D, Zoli W: DNA Methylation profiles as predictors of recurrence in non muscle invasive bladder cancer: an MS-MLPA approach. J Exp Clin Cancer Res. 2013, 32 (1): 94-10.1186/1756-9966-32-94.PubMedCentralCrossRefPubMed
27.
go back to reference Zhu J, Wang Y, Duan J, Bai H, Wang Z, Wei L, Zhao J, Zhuo M, Wang S, Yang L, An T, Wu M, Wang J: DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer. J Exp Clin Cancer Res. 2012, 31: 80-10.1186/1756-9966-31-80.PubMedCentralCrossRefPubMed Zhu J, Wang Y, Duan J, Bai H, Wang Z, Wei L, Zhao J, Zhuo M, Wang S, Yang L, An T, Wu M, Wang J: DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer. J Exp Clin Cancer Res. 2012, 31: 80-10.1186/1756-9966-31-80.PubMedCentralCrossRefPubMed
28.
go back to reference Wang N, Zhang H, Yao Q, Wang Y, Dai S, Yang X: TGFBI promoter hypermethylation correlating with paclitaxel chemoresistance in ovarian cancer. J Exp Clin Cancer Res. 2012, 31: 6-10.1186/1756-9966-31-6.PubMedCentralCrossRefPubMed Wang N, Zhang H, Yao Q, Wang Y, Dai S, Yang X: TGFBI promoter hypermethylation correlating with paclitaxel chemoresistance in ovarian cancer. J Exp Clin Cancer Res. 2012, 31: 6-10.1186/1756-9966-31-6.PubMedCentralCrossRefPubMed
29.
go back to reference Rengucci C, De Maio G, Gardini A, Zucca M, Scarpi E, Zingaretti C, Foschi G, Tumedei M, Molinari C, Saragoni L, Puccetti M, Amadori D, Zoli W, Calistri D: Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence. J Exp Clin Cancer Res. 2014, 33 (1): 65-10.1186/s13046-014-0065-x.PubMedCentralCrossRefPubMed Rengucci C, De Maio G, Gardini A, Zucca M, Scarpi E, Zingaretti C, Foschi G, Tumedei M, Molinari C, Saragoni L, Puccetti M, Amadori D, Zoli W, Calistri D: Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence. J Exp Clin Cancer Res. 2014, 33 (1): 65-10.1186/s13046-014-0065-x.PubMedCentralCrossRefPubMed
30.
go back to reference Moon JW, Lee SK, Lee JO, Kim N, Lee YW, Kim SJ, Kang HJ, Kim J, Kim HS, Park SH: Identification of novel hypermethylated genes and demethylating effect of vincristine in colorectal cancer. J Exp Clin Cancer Res. 2014, 33: 4-10.1186/1756-9966-33-4.PubMedCentralCrossRefPubMed Moon JW, Lee SK, Lee JO, Kim N, Lee YW, Kim SJ, Kang HJ, Kim J, Kim HS, Park SH: Identification of novel hypermethylated genes and demethylating effect of vincristine in colorectal cancer. J Exp Clin Cancer Res. 2014, 33: 4-10.1186/1756-9966-33-4.PubMedCentralCrossRefPubMed
31.
go back to reference Cui X, Zhao Z, Liu D, Guo T, Li S, Hu J, Liu C, Yang L, Cao Y, Jiang J, Liang W, Liu W, Li S, Wang L, Wang L, Gu W, Wu C, Chen Y, Li F: Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma. J Exp Clin Cancer Res. 2014, 33: 20-10.1186/1756-9966-33-20.PubMedCentralCrossRefPubMed Cui X, Zhao Z, Liu D, Guo T, Li S, Hu J, Liu C, Yang L, Cao Y, Jiang J, Liang W, Liu W, Li S, Wang L, Wang L, Gu W, Wu C, Chen Y, Li F: Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma. J Exp Clin Cancer Res. 2014, 33: 20-10.1186/1756-9966-33-20.PubMedCentralCrossRefPubMed
32.
go back to reference Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996, 93 (18): 9821-9826. 10.1073/pnas.93.18.9821.PubMedCentralCrossRefPubMed Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996, 93 (18): 9821-9826. 10.1073/pnas.93.18.9821.PubMedCentralCrossRefPubMed
33.
go back to reference Kinoshita K, Minagawa M, Takatani T, Takatani R, Ohashi M, Kohno Y: Establishment of diagnosis by bisulfite-treated methylation-specific PCR method and analysis of clinical characteristics of pseudohypoparathyroidism type 1b. Endocr J. 2011, 58 (10): 879-887. 10.1507/endocrj.K10E-364.CrossRefPubMed Kinoshita K, Minagawa M, Takatani T, Takatani R, Ohashi M, Kohno Y: Establishment of diagnosis by bisulfite-treated methylation-specific PCR method and analysis of clinical characteristics of pseudohypoparathyroidism type 1b. Endocr J. 2011, 58 (10): 879-887. 10.1507/endocrj.K10E-364.CrossRefPubMed
Metadata
Title
Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non-muscle invasive bladder cancer
Authors
Ying-Li Lin
Yan-Ling Wang
Jian-Guo Ma
Wen-Ping Li
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2014
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-014-0068-7

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